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Recently recognised by the European Commission as a chronic relapsing disease1, obesity affects an increasingly substantial group of people, who faces complications such as diabetes, cardiovascular disease, arthritis or even cancer2. Achieving weight loss is notoriously hard - for many, maintaining a successful weight reduction is even more difficult. Pharmacotherapies for weight management may help people achieve and maintain their optimal body weight.
Building on the experience that started with the glucagon-like peptide-1 (GLP-1) receptor agonist (RA) liraglutide 3.0 mg for once-daily subcutaneous (s.c.) injection, the successor to liraglutide, semaglutide, was recently introduced as an option in weight management as semaglutide 2.4 mg for once-weekly s.c. injection. The underlying clinical development programme is the STEP (Semaglutide Treatment Effect in People with obesity) programme, which comprise a range of completed and ongoing clinical trials.
Below, we introduce the main scientific publications for eight of the STEP trials. Together, the trials corroborated the potential of semaglutide in weight management, extending the well-established clinical utility of the GLP-1 RA from diabetes to obesity/overweight. Throughout the trials, the safety and tolerability profiles of semaglutide were in line with the well-known profiles of the GLP-1 RA drug class.
In addition to the articles detailing the results of each of the completed STEP trials, two review articles have recently been published as well.
In Expert Review of Clinical Pharmacology, le Roux and co-authors describe the pharmacological profile of semaglutide 2.4 mg in chronic weight management, with focus on chemistry, mechanisms of action and the pharmacological properties.
In Obesity, Tahrani and Morton discussed how more-than-modest weight loss likely have benefits on weight-related complications. For example, the authors note how large weight loss (more than 10%) leads to improvements in hypertension and type 2 diabetes as well as knee osteoarthritis, cancer, sleep apnoea, fertility and health-related quality of life.
Published in NEJM, STEP 1 was the pivotal monotherapy phase 3 trial of the clinical development programme and comprised 1961 participants with obesity/overweight, who were randomised (2:1) to once-weekly injections with either semaglutide 2.4 mg or placebo, both as adjunct to lifestyle intervention.
After 68 weeks, participants in the semaglutide group had achieved a weight loss of 14.9% (12.4 %-points placebo-adjusted; p<0.001) compared with baseline. Moreover, 86% of the participants in the semaglutide group lost at least 5% of their baseline body weight; 69% lost 10% or more.
STEP 2 enrolled people with obesity/overweight who were also living type 2 diabetes, a common combination of metabolic diseases. As detailed in The Lancet, the 1210 participants were randomised (1:1:1) to treatment with once-weekly s.c. semaglutide 2.4 mg or 1.0 mg (the dose level of semaglutide when used to improve glycaemic control in type 2 diabetes) or placebo, all as adjunct to lifestyle intervention.
At end of treatment (week 68), participants on semaglutide 2.4 mg had on average achieved a weight loss of 9.6% (6.2 %-points placebo-adjusted; p<0.0001) compared with baseline. Achieving a weight loss of 5% or more was significantly more likely with semaglutide 2.4 mg (69% of the participants) than with placebo (29%).
The 611-participant placebo-controlled STEP 3 trial was reported in JAMA. The trial was similar to STEP 1 but employed more rigorous behavioural therapy regimen, testing if once-weekly s.c. semaglutide 2.4 mg could enhance weight loss achieved via aggressive lifestyle changes.
The combination of semaglutide 2.4 mg and intense behavioural therapy (plus an initial low-calorie diet) allowed participants to lose 16% of their baseline body weight (10.3 %-points placebo-adjusted; p<0.001). In addition, participants on the active treatment (87% of the participants) were significantly more likely to achieve a weight loss of 5% of more than those on placebo (48%).
STEP 4 tested the potential of semaglutide (plus lifestyle intervention) to help people maintain a weight loss. In the trial reported in JAMA, all 902 participants were initially treated with once-weekly s.c. semaglutide 2.4 mg in a 20-week run-in period; then eligible participants were randomised to another 48 weeks of treatment with either semaglutide or placebo.
During the 20-week run-in period, participants on average lost 10.6% of their body weight at trial entry. In the randomised part of the trial, participants on semaglutide had lost 7.9% (vs. week 20), whilst those on placebo had gained 6.9%, corresponding to a treatment difference of 14.8 %-points (p<0.001).
The STEP 5 trial had the longest duration of the STEP trials; during the 104 weeks, the trial enrolling 304 adults with obesity/overweight and no diabetes studied the effects of semaglutide 2.4 mg (plus behavioural intervention) on body weight as well as cardiometabolic risk.
Placebo-adjusted weight loss of up to 16% (p<0.0001) was observed and at least 50% achieved a weight loss of 15% or more. In addition, marked and statistically significant placebo-adjusted reductions in cardiometabolic risk factors were seen; for example, waist circumference was reduced by 9.2 cm, and C-reactive protein and triglycerides decreased by 53% and 22%, respectively. Further, at week 104, semaglutide had markedly reduced the prevalence of prediabetes amongst the trial participants (20% vs. 50% at enrolment).
Published in The Lancet D&E, STEP 6 enrolled 401 adults from Japan and South Korea to study how treatment with once-weekly s.c. semaglutide 2.4 mg affects body weight in people from Asia. In addition, a lower semaglutide dose level of 1.7 mg was tested given the difference between Asian and non-Asian people in terms of body composition and definitions of obesity.
After treatment for 68 weeks (plus lifestyle recommendations), people on semaglutide 2.4 mg and 1.7 mg had lost on average 13.2% (11.1 %-points placebo-adjusted; p<0.0001) and 9.6% (7.5 %-points placebo-adjusted; p<0.0001) of their baseline body weight, respectively.
Comparing the first- and second-generation GLP-1 RA-based weight management drugs, STEP 8 enrolled 338 adults who were randomised to either once-weekly s.c. semaglutide 2.4 mg or once-daily s.c. liraglutide 3.0 mg; both were compared with placebo, and all were given as adjunct to lifestyle intervention.
As reported in JAMA, the weight-loss effect at week 68 of semaglutide 2.4 mg (-15.8% from baseline) was significantly greater than that of liraglutide 3.0 mg (-6.4%) with an estimated treatment difference of -9.4 %-points (p<0.0001). Participants on semaglutide 2.4 mg were also more likely to achieve weight losses of at least 10%, 15% or 20% than those on liraglutide 3.0 mg.
A specific trial in adolescents was conducted. Reported in NEJM, this STEP TEENS trial included 201 people aged 12 to less than 18 years with obesity and compared the effect of once-weekly s.c. semaglutide 2.4 mg to that of placebo on BMI and other weight-related endpoints. Both trial products were given in addition to lifestyle intervention.
After 68 weeks, BMI had decreased significantly (p<0.001) with semaglutide 2.4 mg by 16.1% (compared with an increase of 0.6% with placebo). In addition, the odds of achieving a weight loss of at least 5% was significantly greater (p<0.001 for the odds ratio of 14.0) with semaglutide (73% of participants) than with placebo (18% of participants).
Burki T. Lancet Diabetes Endocrinol. 2021;9(7):418.
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